tetracycle 9a. The same stereoselectivity was observed from the
enolate of the N-unsubstituted 2-indoleacetate 2b, although in this
case the conjugate addition only took place in acceptable yield
(40%) in the presence of CuCN. The resulting epimeric esters 8b
were separately cyclized ( ~ 50%) to give the same enantiopure
tetracycle 9b, thus indicating that epimerization at C-16 had
occurred during cyclization.
The relative configuration of (aR)-8a was unambiguously
established by X-ray crystallography†‡, indicating that the ethyl
substituent had exerted a dramatic influence on the stereochemical
course of the conjugate addition since it had occurred on the Si face
of the carbon–carbon double bond to give an all-trans piperidine
derivative as a consequence of the thermodynamic control.6
Consequently, the absolute configuration at the bridgehead carbons
of tetracycles 9 is the opposite of that present in the uleine
alkaloids.
Scheme 4 Reagents and conditions: (i) n-BuLi, THF, 278 °C, then 7. (ii)
.
Na, liq, NH3, 233 °C, then TiCl4, CH2Cl2, 25 °C. (iii) BH3 Me2S, toluene,
However, the trans stereoselectivity of the above additions
makes accessible tetracyclic derivatives with the natural configura-
tion in the 20-epi series. It is simply a matter of starting from the
enantiomer of 7, taking advantage of the fact that both enantiomers
of phenylglycinol are commercially available. The required
unsaturated lactam ent-7 was prepared in 55% overall yield by
cyclodehydration of (S)-phenylglycinol with racemic methyl
4-formylhexanoate (10), in a process involving a dynamic kinetic
resolution, followed by generation of the carbon–carbon double
bond via a b-ketosulfoxide as in the above R-series (Scheme 3). As
expected, conjugate addition of the enolate derived from 2b to ent-
7, followed by cyclization of the resulting epimeric mixture of
lactam esters ent-8b, led to tetracycle ent-9b, which was chem-
oselectively reduced with Na/liq NH3, to alcohols 12 (64%; 16R/
16S 1 : 2 epimeric mixture) and then converted (53%) to the nor-
20-epiuleine derivative 13 via the corresponding mesylate.
The enantioselective access to the more abundant alkaloids with
a cis H15–H20 relationship required the preparation of an appro-
priate cis-4,5-disubstituted 2-piperidone by stereocontrolled con-
jugate addition to unsaturated lactam 7, avoiding the undesired
equilibration to the more stable trans isomers. For this purpose we
selected the dianion derived from 2-(2-indolyl)-1,3-dithiane7 as the
nucleophile. To our delight, the reaction took place in extraordinar-
ily high yield (90%) and good stereoselectivity (cis/trans ratio 4 :
1), affording the desired enantiopure piperidone cis-14 in 72% yield
after column chromatography (Scheme 4). Treatment of cis-14 with
sodium in liquid ammonia brought about the reductive desulfuriza-
tion and cleavage of the benzylic C–N bond to give a 6-oxylactam,
which was cyclized with TiCl4 to the tetracyclic lactam 15 in 35%
overall yield. Finally, borane reduction of the lactam carbonyl
group followed by treatment of the resulting secondary amine with
reflux, then ClCO2Bn, K2CO3.
benzyl chloroformate gave (40% overall yield) carbamate 16
{[a]25D + 89.0 (c 0.3, CHCl3); lit.2a [a]28D + 89.4 (c 0.4, CHCl3)},
which had previously been converted2a into the alkaloids (+)-dasy-
carpidone and (+)-uleine. Taking into account previous correla-
tions,8,9 the above synthesis also represents a formal total synthesis
of nordasycarpidone, (+)-dasycarpidol and (2)-17-hydroxydihy-
drouleine.
Conjugate addition reactions to phenylglycinol-derived un-
saturated d-bicyclic lactams10 allow the stereocontrolled formation
of C–C bonds at the piperidine 4-position and open short and
efficient routes for the enantioselective construction of the bridged
tetracyclic ring system of uleine alkaloids, both in the normal and
20-epi series.
This work was supported by the DGICYT, Spain (BQU2003-
00505). Thanks are also due to the DURSI, Generalitat de
Catalunya (2001SGR-0084).
Notes and references
‡ Crystal data for C27H30N2O4 (aR)-8a at 294(2) K: M
= 446.53,
orthorhombic, space group P212121, a = 8.931(2), b = 5.990(10), c =
28.080(9) Å, V = 2407.3(10) Å3, Z = 4, m(Mo Ka) = 0.083 mm21, 3440
reflections collected. The final R1 and wR2 were 20.0485 and 0.0981 [I >
2s(I)] and 0.1321 and 0.1451 (all data, respectively). CCDC 263283. See
.cif or other electronic format.
1 (a) M. Alvarez and J. Joule, in Monoterpenoid Indole Alkaloids, J. E.
Saxton, Ed., in The Chemistry of Heterocyclic Compounds, E. C. Taylor,
Ed., Wiley, Chichester 1994; Supplement to 25, Part 4, Chapter 6; (b) M.
Alvarez and J. A. Joule, in The Alkaloids; G. A. Cordell, Ed., Academic
Press, New York, 2001; 57, Chapter 4.
2 (a) M. Saito, M. Kawamura, K. Hiroya and K. Ogasawara, Chem.
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56, 9843.
Scheme 3 Reagents and conditions: (i) Et2O, anh. Na2SO4, 0 °C, 1 h, then
70 °C, 10–15 mm Hg. (ii) C6H5S(O)OMe, KH, THF, reflux, then toluene,
Na2CO3, reflux. (iii) 2b, LDA, THF, 278 °C, then ent-7, HMPA, CuCN, rt.
(iv) TiCl4, CH2Cl2, reflux. (v) Na, liq NH3, 233 °C. (vi) MsCl, Et3N,
CH2Cl2, 0 °C, then DBU, THF, reflux.
C h e m . C o m m u n . , 2 0 0 4 , 1 6 0 2 – 1 6 0 3
1603